Oseni

Alogliptin, pioglitazone.

Oseni tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes: Aloglipitn and piogliztazone.
Each tablet contains alogliptin benzoate 34 mg equivalent to alogliptin 25 mg and pioglitazone hydrochloride 16.53 and 33.06 mg equivalent to pioglitazone 15 and 30 mg, respectively.
Alogliptin: Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C₁₈H₂₁N₅O₂·C₇H₆O₂ and a molecular weight of 461.51 daltons.
Alogliptin benzoate is a white to off-white, crystalline powder, containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol, and very slightly soluble in octanol and isopropyl acetate.
Pioglitazone: Pioglitazone is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance.
Chemically, pioglitazone is prepared as hydrochloride salt, which is identified as (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride. It has a molecular formula of C₁₉H₂₀N₂O₃S·HCl and a molecular weight of 392.90 daltons.
Pioglitazone hydrochloride is an odorless white crystalline powder that contains one asymmetric carbon in the thiazolidinedione moiety. The synthetic compound is a racemate and the two enantiomers of pioglitazone interconvert in vivo. It is soluble in N,N dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
Excipients/Inactive Ingredients: Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, and lactose monohydrate. Film-Coating: Hypromellose, polyethylene glycol, titanium dioxide, talc, ferric oxide (yellow and/or red), and are marked with printing ink (Red A1 or Gray F1).

Pharmacology: Pharmacodynamics: Mechanism of Action: OSENI combines 2 antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes: Alogliptin, a selective inhibitor of DPP-4 and pioglitazone, a member of the TZD class.
Alogliptin: Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Pioglitazone: Pharmacologic studies indicate that pioglitazone improves insulin sensitivity in muscle and adipose tissue while inhibiting hepatic gluconeogenesis. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Alogliptin and Pioglitazone: In a 26-week, randomized, active-controlled study, patients with type 2 diabetes received alogliptin 25 mg coadministered with pioglitazone 30 mg, alogliptin 12.5 mg coadministered with pioglitazone 30 mg, alogliptin 25 mg alone or pioglitazone 30 mg alone. Patients who were randomized to alogliptin 25 mg with pioglitazone 30 mg achieved a 26. 2% decrease in triglyceride levels from a mean baseline of 214.2 mg/dL compared to an 11.5% decrease for alogliptin alone and a 21.8% decrease for pioglitazone alone. In addition, a 14.4% increase in HDL cholesterol levels from a mean baseline of 43.2 mg/dL was also observed for alogliptin 25 mg with pioglitazone 30 mg compared to a 1.9% increase for alogliptin alone and a 13.2% increase for pioglitazone alone. The changes in measures of LDL cholesterol and total cholesterol were similar between alogliptin 25 mg with pioglitazone 30 mg versus alogliptin alone and pioglitazone alone. A similar pattern of lipid effects was observed in a 26-week, placebo-controlled factorial study.
Alogliptin: Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within 2 to 3 hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were 3- to 4-fold greater with alogliptin (at doses of 25-200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8 hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg alone demonstrated decreases in 2-hour postprandial glucose compared to placebo (-30 mg/dL versus 17.3 mg/dL respectively).
Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% across all doses (25 mg, 100 mg, and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.
Pioglitazone: Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower A1C values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin (see Clinical Studies in the following text). Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication (see Precautions and Adverse Reactions).
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the pioglitazone 15 mg, 30 mg, and 45 mg dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 1).

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In the two other monotherapy studies (16-weeks and 24-weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin 16-weeks and 24-weeks) or insulin (16-weeks and 24-weeks), the lipid results were generally consistent with the data previously mentioned.
Clinical Studies: The coadministration of alogliptin and pioglitazone has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone or on metformin alone. There have been no clinical efficacy studies conducted with OSENI; however, bioequivalence of OSENI with coadministered alogliptin and pioglitazone tablets was demonstrated, and efficacy of the combination of alogliptin and pioglitazone has been demonstrated in four Phase 3 efficacy studies.
In patients with type 2 diabetes, treatment with OSENI produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with OSENI appears to be related to the degree of A1C elevation at baseline.
Alogliptin and Pioglitazone Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: In a 26-week, double-blind, active-controlled study, a total of 655 patients inadequately controlled on diet and exercise alone (mean baseline A1C=8.8%) were randomized to receive alogliptin 25 mg alone, pioglitazone 30 mg alone, alogliptin 12.5 mg with pioglitazone 30 mg, or alogliptin 25 mg with pioglitazone 30 mg once daily. Coadministration of alogliptin 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to either alogliptin 25 mg alone or to pioglitazone 30 mg alone (Table 2). Coadministration of alogliptin 25 mg with pioglitazone 30 mg once daily resulted in statistically significant reductions in fasting plasma glucose (FPG) starting from Week 2 through Week 26 compared to either alogliptin 25 mg or pioglitazone 30 mg alone. A total of 3% of patients receiving alogliptin 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving alogliptin 25 mg alone, and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.
Improvements in A1C were not affected by gender, age, or baseline BMI.
The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone (see Table 2).

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Alogliptin and Pioglitazone Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone: In the second 26-week double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C=8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of alogliptin alone; 15 mg, 30 mg, or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin in combination with 15 mg, 30 mg, or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose=1700 mg) during the treatment period. Coadministration of alogliptin and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to alogliptin alone, or to pioglitazone alone when added to background metformin therapy (see Table 3, Figure 1). A total of 4%, 5%, or 2% of patients receiving alogliptin 25 mg with 15 mg, 30 mg, or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving alogliptin 25 mg, and 10%, 15%, or 9% of patients receiving pioglitazone 15 mg, 30 mg, or 45 mg alone required glycemic rescue.
Improvements in A1C were not affected by gender, age, or baseline BMI.
The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone (see Table 3 and Figure 1).

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Alogliptin: Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin in Combination with Pioglitazone: In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C=8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin (mean dose=1700 mg). Patients who failed to meet pre-specified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.
In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at week 26 at Week 52 (Table 4, results shown only for Week 52). A total of 11% of patients who were receiving alogliptin 25 mg in combination with pioglitazone 30 mg and metformin and 22% of patients receiving a dose titration of pioglitazone from 30 mg to 45 mg in combination with metformin required glycemic rescue.
Improvements in A1C were not affected by gender, age, race, or baseline BMI.
The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral (see Table 4).

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Alogliptin: Add-on Therapy to a Thiazolidinedione: A 26-week, placebo-controlled study, was conducted to evaluate the efficacy and safety of alogliptin as add-on therapy to pioglitazone in patients with type 2 diabetes. A total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (mean baseline A1C=8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo. Patients were maintained on a stable dose of pioglitazone (mean dose=30 mg) during the treatment period and those who were also previously treated on metformin (median dose=2000 mg) or sulfonylurea (median dose=10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a 4-week single-blind, placebo run-in period prior to randomization. Following randomization, all patients continued to receive instruction on diet and exercise. Patients who failed to meet pre-specified hyperglycemic goals during the 26-week treatment period received glycemic rescue.
The addition of alogliptin 25 mg once daily to pioglitazone therapy resulted in significant improvements from baseline in A1C and FPG at Week 26, when compared to the addition of placebo (see Table 5). A total of 9% of patients who were receiving alogliptin 25 mg and 12% of patients receiving placebo required glycemic rescue.
The improvement in A1C was not affected by gender, age, baseline BMI, or baseline pioglitazone dose. The mean increase in body weight was similar between alogliptin and placebo when given in combination with pioglitazone. Lipid effects were neutral (see Table 5).

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Pharmacokinetics: Absorption and Bioavailability: Alogliptin and Pioglitazone: In bioequivalence studies of OSENI 12.5 mg/15 mg and 25 mg/45 mg, the AUC and maximum concentration (C_max) of both the alogliptin and the pioglitazone component following a single dose of the combination tablet (12.5 mg/15 mg or 25 mg/45 mg) were bioequivalent to alogliptin (12.5 mg or 25 mg) concomitantly administered with pioglitazone (15 mg or 45 mg respectively) tablets under fasted conditions in healthy subjects.
Administration of OSENI 25 mg/45 mg with food resulted in no significant change in overall exposure of alogliptin or pioglitazone. OSENI may therefore be administered with or without food.
Alogliptin: The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal result in no change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food.
Pioglitazone: Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within 2 hours. Food slightly delays the time to peak serum concentration (T_max) to 3 to 4 hours, but does not alter the extent of absorption (AUC).
Distribution: Alogliptin: Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.
Alogliptin is 20% bound to plasma proteins.
Pioglitazone: The mean apparent V_d/F of pioglitazone following single-dose administration is 0.63±0.41 (mean±SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Metabolism: Alogliptin: Alogliptin does not undergo extensive metabolism and 60-71% of the dose is excreted as unchanged drug in the urine.
Two minor metabolites were detected following administration of an oral dose of [¹⁴C] alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite, and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that the CYP2D6 and CYP3A4, contribute to the limited metabolism of alogliptin.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.
Pioglitazone: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans. Following once daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within 7 days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
Maximum serum concentration (C_max), AUC, and trough serum concentrations (C_min) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor showed that pioglitazone is a CYP2C8 substrate (see Dosage & Administration and Interactions). Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Excretion and Elimination: Alogliptin: The primary route of elimination of [¹⁴C] alogliptin derived radioactivity occurred via renal excretion (76%) with 13% recovered in the feces achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systematic clearance was 14.0 L/hr.
Pioglitazone: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.
Special Populations: Renal Impairment: Alogliptin: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment [creatinine clearance (CrCl) ≥60 to <90 mL/min], an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.
In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate 2-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dose of OSENI is 12.5 mg/15 mg, 12.5 mg/30 mg, or 12.5 mg/45 mg once daily in patients with moderate renal impairment.
In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (CrCl <15 mL/min or requiring dialysis), and approximate 3- and 4-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a 3-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD. Coadministration of pioglitazone and alogliptin 6.25 mg once daily based on individual requirements may be considered in these patients.
Pioglitazone: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore no dose adjustment in patients with renal impairment is required.
Hepatic Impairment: Alogliptin: Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease (see Precautions).
Pioglitazone: Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use caution in patients with liver disease (Precautions).
Gender: Alogliptin: No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: The mean C_max and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, A1C decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Geriatric: Alogliptin: No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about 7 hours). These changes were not of a magnitude that would be considered clinically relevant. 
Pediatrics: Alogliptin: Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.
Pioglitazone: Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients (see Use in Children under Precautions).
Race and Ethnicity: Alogliptin: No dose adjustment is necessary based on race. Race (White, Black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: Pharmacokinetic data among various ethnic groups are not available.
Drug-Drug Interactions: Coadministration of alogliptin 25 mg once daily with a CYP2C8 substrate, pioglitazone 45 mg once daily for 12 days had no clinically meaningful effects on the pharmacokinetics of pioglitazone and its active metabolites. Specific pharmacokinetic drug interaction studies with OSENI have not been performed, although such studies have been conducted with the individual components of OSENI (alogliptin and pioglitazone).
Alogliptin: In Vitro Assessment of Drug Interactions: In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.
In Vivo Assessment of Drug Interactions: Effects of Alogliptin on Other Drugs: In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (see Figure 2). No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies (see Figure 2).

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Effects of Other Drugs on the Pharmacokinetics of Alogliptin: There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described in Figure 3 and Tables 6 and 7 (see Figure 3, Tables 6 and 7).

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Non-Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Alogliptin and Pioglitazone: No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with OSENI. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.
Alogliptin: Rats were administered oral doses of 75, 400, and 800 mg/kg alogliptin for 2 years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150, or 300 mg/kg alogliptin for 2 years, or up to approximately 51-times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating, or fertility, at doses up to 500 mg/kg, or approximately 172-times the clinical dose based on plasma drug exposure (AUC).
Pioglitazone: A two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the MRHD of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m²). A two year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 11 times the MRHD based on mg/m²). No drug-induced tumors were observed in any organ.
Pioglitazone was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone daily prior to and throughout mating and gestation (approximately 9 times the MRHD based on mg/m²).
Animal Toxicology and/or Pharmacology: Pioglitazone: Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone (approximately 11, 1, and 2 times the MRHD for mice, rats, and dogs, respectively, based on mg/m²). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg (approximately 35 times the MRHD based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the MRHD based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the MRHD based on mg/m²).

Monotherapy and Combination Therapy: OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings when treatment with both alogliptin and pioglitazone is appropriate (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Important Limitations of Use: OSENI should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Use with caution in patients with liver disease (see Precautions).

Oseni should be taken once daily and can be taken with or without food.
The recommended starting dose for OSENI (alogliptin/pioglitazone): Patients Inadequately Controlled on Diet and Exercise: 25 mg/15 mg or 25 mg /30 mg.
Patients Inadequately Controlled on Metformin Monotherapy: 25 mg/15 mg or 25 mg/30 mg.
Patients on Alogliptin who require Additional Glycemic Control: 25 mg/15 mg or 25 mg/30 mg.
Patients on Pioglitazone who require Additional Glycemic Control: 25 mg/15 mg or 25 mg/30 mg as appropriate based upon current therapy.
Patients Switching from Alogliptin Co-Administred with Pioglitazone: OSENI may be initiated at the dose of alogliptin and pioglitazone based upon current therapy.
Patients with Congestive Heart Failure (NYHA Class I or II): 25 mg/15 mg.
The OSENI dose can be titrated up to a maximum of 25 mg/30 mg once daily based on glycemic response as determined by hemoglobin A1c (A1C).
After initiation of OSENI or with dose increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone, (e.g., weight gain, edema, and signs and symptoms of congestive heart failure) (see Warnings and Precautions).
Renal Impairment: No dose adjustment of OSENI is necessary for patients with mild renal impairment [creatinine clearance (CrCl) ≥60 mL/min].
The dose of OSENI is 12.5 mg/15 mg or 12.5 mg/30 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).
OSENI is not recommended for patients with severe renal impairment OSENI or ESRD (see Pharmacology: Pharmacokinetics under Actions).
Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of OSENI therapy and periodically thereafter.
Coadministration with Strong CYP2C8 Inhibitors: Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of OSENI is 25 mg/15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors (see Pharmacology: Pharmacokinetics under Actions and Interactions).
Administration: Oral use. The tablets must not be split before swallowing.

Alogliptin: The highest doses of alogliptin administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the recommended clinical dose of 25 mg, respectively). No serious adverse events were observed at these doses.
In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.
Alogliptin is minimally dialyzable; over a 3-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis.
Pioglitazone: During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

History of serious hypersensitivity reaction to alogliptin or pioglitazone, components of OSENI, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.
Do not initiate in patients with NYHA Class III or IV heart failure (see Warnings).

CONGESTIVE HEART FAILURE: Thiazolidinediones, including pioglitazone cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, fatigue and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.
Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone in patients with established NYHA Class III or IV heart failure is contraindicated.
RISK OF URINARY BLADDER CANCER: This drug may increase risk of bladder cancer.
This drug should not be used in patients with active bladder cancer.
This drug should be used with caution, by considering the benefits and risks in patients who have bladder cancer or are at risk of having bladder cancer. The use of pioglitazone for more than 1 year may be associated with an increase risk of bladder cancer.
Consult physician if the patient have any signs or symptoms of blood in urine, urinary urgency, pain on urination, or back or abdominal pain.
Warnings (MOPH announcement): This drug is contraindicated in patients with severe congestive heart failure (NYHA class III and IV). This drug may cause congestive heart failure. If dyspnea, fatigue, rapid increase in body weight or excess edema develops after taking this drug, a physician should be consulted immediately.
Pioglitazone should be used with caution with NSAIDs, Coxibs and insulin as concomitant use with these medications may increase the risk of heart failure and edema.
This drug may increase risk of bladder cancer.
Should not be used this drug in patients with active bladder cancer.
This drug should be used with caution, by considering the benefits and risks in patients who have bladder cancer or are at risk of having bladder cancer. The use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer.
Consult the physician if patient has any signs or symptoms of blood in urine, urinary urgency, pain on urination, or back or abdominal pain.

Congestive Heart Failure: Pioglitazone: Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered (see Contraindications, Warnings and Adverse Reactions).
Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking alogliptin. After initiation of OSENI, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, OSENI should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using OSENI.
Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue OSENI, assess for other potential causes for the event, and institute alternative treatment for diabetes (see Adverse Reactions). Use caution in patients with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with OSENI.
Hepatic Effects: There have been postmarketing reports of fatal and non-fatal hepatic events in patients taking pioglitazone or alogliptin, although the reports contain insufficient information necessary to establish the probable cause (see Adverse Reactions). There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date (see Adverse Reactions). In randomized controlled studies of alogliptin, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel [ALT, aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin] and assessing the patient is recommended before initiating OSENI therapy. In patients with abnormal liver tests, OSENI should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), OSENI treatment should be interrupted and an investigation done to establish the probable cause. OSENI should not be restarted in these patients without another explanation for the liver test abnormalities.
Edema: Pioglitazone: In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related (see Adverse Reactions). In postmarketing experience, reports of new onset or worsening of edema have been received.
OSENI should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, OSENI should be used with caution in patients at risk for congestive heart failure. Patients treated with OSENI should be monitored for signs and symptoms of congestive heart failure (see Warnings).
Fractures: Pioglitazone: In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.
Urinary Bladder Tumors: Pioglitazone: Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study (see Pharmacology: Non-Clinical Toxicology under Actions). In two 3-year trails in which pioglitazone was compared to placebo or glibenclamide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo.
A five year interim report of an ongoing 10-year observational cohort study found a nonsignificant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone [HR 1.2 (95% Cl 0.9-1.5)]. Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increase in risk [HR 1.4 (95% Cl 0.9-2.1)], which reached statistical significance after more than 24 months of pioglitazone use [HR 1.4 (95% Cl 1.03-2.0)]. Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 [from approximately 7 in 10,000 (without pioglitazone) to approximately 10 in 10,000 (with pioglitazone)].
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer.
Use with Medications Known to Cause Hypoglycemia: Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with OSENI.
Macular Edema: Pioglitazone: Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see Adverse Reactions).
Ovulation: Pioglitazone: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking OSENI (see Pregnancy and Lactation). This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with OSENI is recommended.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with OSENI or any other antidiabetic drug.
Hepatic Impairment: Alogliptin: No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use with caution when administering alogliptin to patients with liver disease.
Pioglitazone: No dose adjustments are required in patients with hepatic impairment (Child-Pugh Grade B/C) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. However, use caution in patients with liver disease (see previously mentioned text).
Use in Children: Safety and effectiveness of OSENI in pediatric patients have not been established.
OSENI is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors (see previously mentioned text).
Use in Elderly: Alogliptin and Pioglitazone: Of the total number of patients (N=1533) in clinical safety and efficacy studies treated with alogliptin and pioglitazone, 248 (16.2%) patients were 65 years and older and 15 (1%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded.
Alogliptin: Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with alogliptin, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients.
Pioglitazone: A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26-week double-blind, placebo-controlled, monotherapy, trials were ≥65 years old and 2 patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive, 1068 patients (41%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients although small sample sizes for patients ≥75 years old limit conclusions (see Pharmacology: Pharmacokinetics under Actions).

Use in Pregnancy: Pregnancy Category C: Alogliptin and Pioglitazone: There are no adequate and well-controlled studies in pregnant women with OSENI or its individual components. Based on animal data, the likelihood that OSENI increase the risk of developmental abnormalities is predicted to be low. OSENI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When administered to rats during organogenesis the combination treatment with alogliptin and pioglitazone (100 mg/kg alogliptin plus 40 mg/kg pioglitazone) slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights, but did not result in embryo-fetal mortality or teratogenicity.
Alogliptin: Alogliptin, administered to pregnant rabbit and rats during the period of organogenesis was not teratogenic at doses of up to 200 and 500 mg/kg, or 149-times and 180-times, respectively, the clinical dose based on plasma drug exposure (AUC).
Doses of alogliptin up to 250 mg/kg (approximately 95-times clinical exposure based on AUC) given to pregnant rats from gestation day 6 to lactation day 20 did not harm the developing embryo or adversely affect growth and development of offspring.
Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
Pioglitazone: In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the MRHD based on body surface area (mg/m²); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m² basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately 2 or more times the MRHD (mg/m² basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m² basis).
Use in Lactation: No studies have been conducted with the combined components of OSENI. In studies performed with the individual components, both alogliptin and pioglitazone are secreted in the milk of lactating rats. It is not known whether alogliptin and/or pioglitazone are secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for OSENI to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue OSENI, taking into account the importance of OSENI to the mother.

Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Alogliptin and Pioglitazone: Over 1500 patients with type 2 diabetes have received alogliptin co-administered with pioglitazone in four large randomized, double-blind controlled clinical trials. The mean exposure to OSENI was 29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two placebo-controlled studies of 16 to 26 weeks duration and two active controlled studies of 26 weeks and 52 weeks in duration. In the OSENI arm, the mean duration of diabetes was approximately 6 years, the mean body mass index (BMI) was 31 kg/m² (54% of patients had a BMI ≥30 kg/m2), and the mean age was 54 years (16% of patients ≥65 years of age).
In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse events was 65% in patients treated with OSENI compared to 57% treated with placebo. Overall discontinuation of therapy due to adverse events was 2.5% with OSENI compared to 2.0% with placebo, 3.7% with pioglitazone or 1.3% with alogliptin.
Adverse reactions reported in ≥4% of patients treated with OSENI and more frequently than in patients who receive alogliptin, pioglitazone or placebo are summarized in Table 8 (see Table 8).

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Alogliptin: Add-on Therapy To a Thiazolidinedione: In addition, in a 26-week, placebo-controlled, double-blind study, patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%).
Hypoglycemia: In a 26-week placebo-controlled factorial study with alogliptin in combination with pioglitazone on background therapy with metformin the incidence of subjects reporting hypoglycemia was 0.8%, 0%, 3.8% for alogliptin 25 mg with pioglitazone 15 mg, 30 mg, or 45 mg, respectively; 2.3% for alogliptin 25 mg; 4.7%, 0.8%, 0.8% for pioglitazone 15 mg, 30 mg, or 45 mg, respectively; and 0.8% for placebo.
In a 26-week, active-controlled, double-blind study with alogliptin alone, pioglitazone alone or alogliptin coadministratered with pioglitazone in patients inadequately controlled on diet and exercise, the incidence of hypoglycemia was 3% on alogliptin 25 mg with pioglitazone 30 mg, 0.6% on alogliptin 25 mg, and 1.8% on pioglitazone 30 mg.
In a 52-week, active-controlled, double-blind study of alogliptin as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the incidence of subjects reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg and metformin group.
Alogliptin: Approximately 8500 patients with type 2 diabetes have been treated with alogliptin in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to alogliptin was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina, and 7% had a history of congestive heart failure. The mean duration of diabetes was 7 years, the mean body mass index (BMI) was 31 kg/m² (51% of patients had a BMI ≥30 kg/m²), and the mean age was 57 years (24% of patients ≥65 years of age).
Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with alogliptin 12.5 mg daily, alogliptin 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione, and with insulin.
Five placebo-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy.
Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.
In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with alogliptin 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with alogliptin 25 mg compared to 4.5% with placebo or 6.2% with active comparator.
Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 9 (see Table 9).

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Pancreatitis: In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving alogliptin 25 mg daily compared to 5 of 5183 (<0.1%) patients receiving all comparators.
Hypersensitivity Reactions: In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with alogliptin 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with alogliptin 25 mg.
Hypoglycemia: Hypoglycemia events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glibenclamide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide.
Pioglitazone: Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for 6 months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least 2 years.
Common Adverse Events: 16 to 26-Week Monotherapy Trials: A summary of the incidence and type of common adverse events reported in three pooled 16 to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 10. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to pioglitazone dose (see Table 10).

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Congestive Heart Failure: A summary of the incidence of adverse events related to congestive heart failure for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials were (at least one congestive heart failure, 0.2% to 1.7%; hospitalized due to congestive heart failure, 0.2% to 0.9%). None of the events were fatal.
Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (N=262) or glibenclamide at daily doses of 10 mg to 15 mg (N=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 11 (see Table 11).

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Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 12 (see Table 12).

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Cardiovascular Safety: In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean A1C of 8.1%. Mean duration of follow-up was 34.5 months.
The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, non-fatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).
Although there was no statistically significant difference between pioglitazone and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 13 (see Table 13).

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Weight Gain: Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Edema: Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure.
Hepatic Effects: There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing pioglitazone to glibenclamide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than 3 times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glibenclamide developed ALT values >3 times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT >3 times the upper limit of the reference range and a corresponding total bilirubin >2 times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
Hypoglycemia: In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo. The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%). Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (N=2) or pioglitazone 30 mg or 45 mg in combination with insulin (N=12).
Urinary Bladder Tumors: Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study (see Pharmacology: Nonclinical Toxicology under Actions). In two 3-year trials in which pioglitazone was compared to placebo or glibenclamide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.
Laboratory Abnormalities: Alogliptin: No clinically meaningful changes in hematology, serum chemistry, or urinalysis were observed in patients treated with alogliptin.
Pioglitazone: Hematologic Effects: Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.
Creatine Phosphokinase: During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in 9 (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patient. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.
Postmarketing Experience: Alogliptin: The following adverse reactions have been identified during the postmarketing use of alogliptin outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and severe cutaneous adverse reactions including Stevens-Johnson syndrome; hepatic enzyme elevations; fulminant hepatic failure; and acute pancreatitis.
Pioglitazone: The following adverse reactions have been identified during the postmarketing use of pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
New onset or worsening diabetic macular edema with decreased visual acuity (see Precautions).
Fatal and non-fatal hepatic failure (see Precautions).
Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.
In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure (see Warnings and Precautions).

Alogliptin: Alogliptin is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested, or with renally excreted drugs (see Pharmacology: Pharmacokinetics under Actions).
Strong CYP2C8 Inhibitors: Pioglitazone: An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the concentration-time curve or AUC) and half-life of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
CYP2C8 Inducers: Pioglitazone: An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with OSENI, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone (see Pharmacology: Pharmacokinetics under Actions).

Store below 30°C.

Antidiabetic Agents

A10BD09 - pioglitazone and alogliptin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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